OCRL and the pathogenesis of Lowe Syndrome and Dent Disease

OCRL 与 Lowe 综合征和 Dent 病的发病机制

• 批准号: 8577200
• 负责人: Pietro De Camilli
• 金额: $ 28.97万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8577200
• 关键词: Aarskog syndrome; Actins; Affect; Apical; Back; Cell Line; Cell membrane; Cell physiology; Cells; Cilia; Clinical; Cytokinesis; Defect; Disease; Endocytosis; Enzymes; Event; Family; Fanconi Syndrome; Functional disorder; Genes; Goals; Homeostasis; Homologous Gene; Impairment; Inositol; Intracellular Accumulation of Lipids; Intracellular Membranes; Ion Exchange; Kidney; Kidney Diseases; Knowledge; Light; Link; Medical; Membrane; Membrane Protein Traffic; Membrane Proteins; Mental Retardation; Modeling; Molecular; Mouse Cell Line; Mus; Mutation; Oculocerebrorenal Syndrome; Pathogenesis; Pathway interactions; Phenotype; Phosphatidylinositols; Phospholipids; Phosphoric Monoester Hydrolases; Physiological; Polyphosphates; Positioning Attribute; Protein Family; Proteins; Proximal Kidney Tubules; Recycling; Regulation; Role; Sorting - Cell Movement; Surface; Testing; Therapeutic; Work; arm; congenital cataract; enzyme activity; feeding; glomerular filtration; human disease; inositol-1,4,5-trisphosphate 5-phosphatase; loss of function; loss of function mutation; member; neuronal cell body; protein transport; public health relevance; therapy design; trafficking; treatment strategy

DESCRIPTION (provided by applicant):The long-term goal of this proposal is to develop therapeutic strategies for the treatment of two human diseases, Oculo-Cerebro-Renal syndrome of Lowe (Lowe syndrome) and Dent disease, which result from loss-of-function mutations in the gene encoding the inositol 5-phosphatase OCRL. Lowe syndrome is a severe X-linked disorder characterized by reabsorption defects in the kidney proximal tubule (renal Fanconi syndrome), mental retardation and congenital cataracts. Dent disease is another X-linked disorder in which the clinical manifestations are limited to kidney defects that are similar to those observed in Lowe syndrome. While it is known that the main function of OCRL, an enzyme expressed by all cells of the body, is to dephosphorylate two bilayer phospholipids, PI(4,5)P2 and PI(3,4,5)P3 (members of the phosphoinositide family) at the 5 position of their inositol ring, the mechanisms through which a defect in the catalytic activity of this enzyme cause disease, and specifically kidney disease, remain unclear. The objective of this project is to elucidate such mechanisms. Strong evidence indicates that a main function of OCRL is to avoid accumulation of its substrates on membranes of the endocytic pathway. It is hypothesized that the resulting inappropriate intracellular accumulation of these lipids, primarily PI(4,5)P2, leads to ectopic actn nucleation and abnormal traffic and sorting of membrane proteins along the endocytic pathway. This effect is expected to have a dramatic impact on proximal tubule cells due the massive endocytic activity occurring at their actinrich apical pole. In this proposal we plan to elucidate he physiological function of the intracellular phosphoinositide pools controlled by OCRL, to determine how such pools regulate actin nucleation and endosomal traffic, and to establish how these events specifically affect the function of kidney proximal tubule cells in model mouse and cell lines.

描述（由申请人提供）：该提案的长期目标是开发治疗两种人类疾病的治疗策略，即劳氏眼脑肾综合征（Lowe 综合征）和 Dent 病，这些疾病是由编码肌醇 5-磷酸酶 OCRL 的基因功能丧失突变引起的。 Lowe 综合征是一种严重的 X 连锁疾病，其特征是肾近曲小管重吸收缺陷（肾范可尼综合征）、智力低下和先天性白内障。 Dent 病是另一种 X 连锁疾病，其临床表现仅限于肾脏缺陷，与 Lowe 综合征中观察到的相似。虽然已知 OCRL（一种由身体所有细胞表达的酶）的主要功能是使两个双层磷脂 PI(4,5)P2 和 PI(3,4,5)P3（磷酸肌醇家族的成员）在其肌醇环的 5 位去磷酸化，但该酶催化活性缺陷导致疾病的机制，以及 特别是肾脏疾病，目前尚不清楚。该项目的目标是阐明此类机制。有力的证据表明 OCRL 的主要功能是避免其底物在内吞途径膜上的积累。据推测，这些脂质（主要是 PI(4,5)P2）在细胞内不适当的积累会导致异位肌动蛋白成核以及膜蛋白沿内吞途径的异常运输和分类。由于富含肌动蛋白的顶端发生大量内吞活动，这种效应预计会对近端小管细胞产生巨大影响。在本提案中，我们计划阐明 OCRL 控制的细胞内磷酸肌醇池的生理功能，以确定这些池如何调节肌动蛋白成核和内体运输，并确定这些事件如何具体影响模型小鼠和细胞系中肾近曲小管细胞的功能。